CA2051815A1 - Magnetic resonance imaging agents - Google Patents

Abstract

NOVEL MAGNETIC RESONANCE IMAGING AGENTS Abstract of the Disclosure Novel magnetic resonance imaging agents comprise complexes of paramagnetic ions with hydrazide derivatives of polyaminocarboxylic acid chelating agents. These novel imaging agents are characterized by excellent NMR image-contrasting properties and by high solubilities in physiological solutions. A novel method of performing an MMR diagnostic procedure involves administering to a warm-blooded animal an effective amount of a complex as described above and then exposing the warm-blooded animal to an MMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal.

Description

2 ~ 5 ~ 8 :1~

NOVEL MAGNETIC RESONANCE IMAGINt; AGENTS

Backqround of the Invention This invention relates to nuclear magnetic resonance (NMR) imaging and, more particularly, to method~ and compo~itions for enhancing NMR imaging.
The recently developed technique of NMR imaging encompa6~es the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to x-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. A~ currently used, the images produced constitute a map of the proton density distribution and/or their relaxation times in organs and tissues. The technique of NMR imaging i8 advantageou~31y non-invasive as it avoids the u~e of ionizing radiation.
While l;he phenomenon of NMR wa~ Al~covered in 1945, it is only relatively recently that it has found application as a means of mapping the internal structure of the body as a re~ult of the original sugyestion of ~auterbur ~Nature, 242, 190-191 (1973)).
The fundame~lltal lack of any known hazard associated with the level of the magnetic and radio-frequency field~ that are employed renders it po~sible to make repeated scans on vulnerable individual~. In addition 2~ 8~ 3 to standard ~can plane~ laxial, coronal, and sagittal), oblique scan planes can also be selected.
In an NMR experiment, the nuclei under ~tudy in a sample (e.g. protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei, as they relax, subsequently emit RF at a sharp resonance frequency.
The resonance frequency of the nuclei depends on the applied magnetic field.
According to known principles, nuclei with appropriate spin, when placed in an applied magnetic field (B, expressed generally in units of gauss or Tesla (10~ gauss)) align in the direction of the field.
In the case of protons, these nuclei prece~s at a frequency, f, of 42.6 MHz at a field strength of 1 Tesla. At this frequency, an RF pulqe of radiation will excite the nuclei and can be considered to tip the net magnetization out of the field direction, the extent of thi6 rotation being determined by the pulse duration and energy. Aiter the RF pulse, the nuclei ~Irelax~ or return to equilibrium with the magnetic field, emitt:ing radiation at the resonant frequency.
The decay oi. the emitted radiation is characterized by two relaxati.on times, i.e., Tl, the ~pin-lattice relaxation time or longitudinal rolaxation tlme, ~h~t is, the time taken by the nucloi to r~turn to equilibrium along the direc~lon of the externally applied magnetic field, and T2, the 8pin-Bpin relaxation time as~ociated with the depha~ing of the initially coherent precession of indlvidual proton spins. These relaxation times have been e~tablished for various fluids, organs and tissues in different species of mammals .

2 ~

In NMR imaglng, ~canning planes and slice thicknesses can be selected. This selection permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in NMR imaging equipment promotes a high reliability.
It is believed that NMR imaging has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, x-xay attenuation coefficients alone determine image contrast, whereas at least five separate variables (Tl, T2, proton density, pulse sequence and flow) may contribute to the NMR signal. For example, it has been shown (Damadian, Science, 171, 1151 (1971)) that the values o the Tl ~nd T2 relaxation in tissues are generally longer by about a factor of 2 in excised specimens of neoplastic tissue compared with the host tissue.
By reason of its sensitivity to subtle physicochemical differences between organs and/or tissues, it i8 believed that NMR may be capable of differentiating different tissue types and in detecting diseases which induce physicochemical changes that may not be detected by x-ray or CT which are only sensitive to differences ln the electron density of tissue.
As noted above, two of tho principal im~ging parameters are the relaxation times, T~ and T2. For protons (or other appropriate nuclei), these relaxation times are influenced by the environment of the nuclei (e.g., vi~cosity, temperature, and the like). These two relaxatlon phenomena are essentially mechanisms whereby the initially imparted radiofrequency energy is dissipated to the surrounding environment. The rate of this energy 1088 or relaxation can be influenced by certain other nuclei which are paramagnetic. Chemical compounds incorporating the~e paramagnetic nuclei may substantially alter the Tl and T2 values for nearby proton~. The extent of the paramagnetic effect of given chemical compound i8 a function of the environment within which it finds itself.
In general, paramagnetic divalent or trivalent ions of elements with an atomic number of 21 to 29, 42 to 44 and 58 to 70 have been found effectLve as NMR
image contrasting agents. Suitable such ion~ include chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), pra~eodymium (III), neodymium (III), samarium (III) and ytterbium (III). Because of their very ~trong magnetic moments, gadolinium (III), terbium (III), dy~prosium (III), holmium (III) and erbium (III) are preferred. Gadolinium (III) ion~ have been particularly preferred as NMR image contrastlnq agents.
Typically, the dlvalent and trivalent paramagnetic ions have been administered in the form of complexe~
with organic complexing agent~. Such complexes provide the paramagnetic ions in a ~oluble, non-toxic form, and facilitate their rapid clearance from the body following the imaging procedure. Grie~ et al., U.S.
patent 4,641,447, disclose complexos o~ variou~
paramagnetic ions with conventional aminocarboxylic acid complexing agent~. A preferred complex disclosed by Gries et al. i8 the complex of gadolinium (III) with diethylenetriaminepentaacetic acid ("DTPA"). Thi~
complex may be repre~ented by the formula:

~05 1 ~3 s _ _ ~ CH2-CH2-N

-OOC -CH2-N Gd~
\ CH2-C00-_ Paramagnetic ions, such as gadolinium (III), have been found to form strong complexes with DTPA. The~e complexes do nst di~sociate substantially in phy~iological aqueouq fluids. The complexes have a net charge of -2, and generally are administered as ~oluble salts. Typical such salts are the sodium and N-methylglucamine salts.
The administration of ionizable salts is attended by certain di~advantages. These salts can raise the in vivo ion concentration and cause localized disturbances in osmolality, which in turn, can lead to edema and other undesirable reactions.
Efforts have been made to deelgn non-ionic paramagnetic lon complexes. In ganeral, this goal ha~
been achieveci by converting one or more of the free carboxylic ac~id groups of the complexing agent to neutral, non--ionizable group~. For example, S.C. Quay, in U.S. patents 4,687,658 and 4,687,659, disclo~es alkylester and alkylamide derivatives, respectively, of DTPA complexe~. Similarly, published West German applications P 33 24 235.6 and P 33 24 236.4 disclose 2 ~

mono- and polyhydroxyalkylamide derivatives of DTPA and their use as complexing agents for paramagne~ic ions.
The nature of the derivative used to convert carboxylic acid groups to non-ionic groups can have a ~ignificant impact on tissue specificity.
Hydrophilic complexes tend to concentrate in the interstitial fluids, whereas lipophilic complexes tend to associate with cells. Thus, differences in hydrophilicity can lead to different applications of the compounds. See, for example, ~einmann et al., AJR, 142, 679 (Mar. 1984) and Brasch et al., ~JR, 142, 625 (Mar~ 1984).
Thus, a need continues to exist for new and ~tructurally diverse non-ionic complexes of paramagnetic ions for use as NMR imaging agents. There i8 further a need ln the art to develop highly stable complexes with good relaxivity characteri-~tics.

Summary of the Invention The present invention provides novel complexing agents and complexes of complexing agents with paramagnetic ions. The complexes are represented by the following formula:

O O
Rl-C-CH2 CH2~C-RI
0 N-A-N 0 M~Z
Rl-C-CHz C~2-l-R~

wherein A is -CHR2-C~I- or 2 u' ~

-CH2CH2NCH2cH2-M~Z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of +2 or +3; R~ group~ may be the same or different and are 6elected from the group consisting of -0~ and R~ R5 I /

-N-N

lS wherein R4, R5, and R6may be the same or different and are hydroyen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atom~, or R5 and R6 can together with the ad~acent nitrogen form a heterocyclic ring of five, 5iX or seven members, wherein 0 or 1 members other than the o nitrogen are -O-, -S-, -S- or -N- and which members are O R
unsubatitute~d or 6ub~tituted by hydroxy, alkyl, aryl, hydroxyalkyl., aminoalkyl, aminoaryl, ~lkylamino, or carbamoyl wherein the substituents contain from l to about 6 carbon atoms, or R~ and Rs can together with the nitrogens to which each i8 attached form a hetQrcyclic ring of five, six or seven members, wherein O to l membRrs other than the nitrogens are 2 ~

-O-, -S-, S-, or -N-1 l7 and which members are un~ub~tituted or ~ubstituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atom~;
R2 and R3 may be the same or different and are hydrogen, alkyl having f rom 1 to about 6 carbon atoms, phenyl or benzyl;
R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portionY contain from l to about 6 carbon atoms;
and wherein 2 or 3 of the Rl groups are -O~and the remainder of the Rl groups are R~ R5 -N-N
\R6 In one embodiment, R5 and R6 together form a heterocyclic ring of the formul~ ~N X wherein X i~
a 6ingle bond, O
-CH2-, -O-, -S-, -S- or -N-O R

In other embodiments t wherein R~and R5 together with the nitrogens to which each i~ attached form a heterocyclic ring, the heterocyclic ring may have the formula /
-N ~ ~ or -N
1 6 Rl6 wherein ~6 i8 as defined above.
Also disclosed i8 a method of performing an NMR
diagnostic procedure which involves administering to a warm-blooded animal an effective amount of the above-described complex and then exposing the warm-blooded animal to an MMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
Detsiled Descri~tion of the Invention The complexing agents employed in this invention are derivatives of well-known polyaminocarboxylic acid chelating agent~, such as DTPA and ethylenediaminetetraacetic acid ("EDTA"). In these derivatives, some carboxylic acid groups of the polyaminocarboxylic acid are converted to hydrazide groups, ~uch as tho3e of the formula, O R'' R5 -C--N-N . Thu3, if the paramagnetic ion i~
\R6 trivalent a~d the chelating aqent is DTPA, two of the carboxylic acid groups will be derivatized to the hydrazide form. Likewise, if the paramagnetic ion is divalent, three of the carboxylic acid group~ of DTPA
or two of the carboxylic acid group~ of EDTA will be derivatized to the hydrazide form. When reacted with a divalent or trivalent paramagnetic ion, the resulting 2 ~ 3 complexes are sub~tantlally non-ionic as evidenced by very low electrical conductivity.
The hydrazide derivatives of the chelating agents are prepsred in a conventional manner. One process for preparing hydrazide derivative~ 18 set forth in U.S.P.
No. 3,787,482. In general, they are prepared by reacting a stoichiometric amount of a mono-, di-, or tri-substituted hydrazino compound of the formula R~

HN-NR R with a reactive derivative of the polyaminocarboxylic acid chelating agent under hydrazide-forming conditions. Such reactive derivatives include, for example, anhydride~, mixed anhydride~ and acid chlorides. As noted above, R5 and R6 togethex with the ad~acent nitrogen may form a heterocyclic ring of five, six or seven members. This embodiment results in compounds containing ~ hydrazide functional group external to the ring structure. In another embodiment, R~ and R5 together with the nitrogens to which each is attached form a heterocyclic ring of five, 8iX or seven members. In this embodiment, the hydrazide functional group is internal to the ring etructure. This ring can be saturated or unsaturated and substituted or unsub~tltuted. If the heterocyclic ring is substituted, tho total number of 8UbRtitUent~ typiCAlly i8 1 to 3. Example~ of suitable heterocyclic rings include pyrrolidlnyl, pyrrolyl, pyrazolidinyL, pyrazolinyl, pyridyl, p$peridyl, piperazinyl, morpholinyl, etc.
In one embodiment, the reactions for preparing the hydrazide derivatives of the present invention are conducted in an organic solvent at an elevated temperature. Suitable solvents include those in which the reactants are ~ufficiently ~oluble and which are s~lbstantially unreactive with the reactants and products. Lower aliphatic alcohols, ketone~, ethers, esters, chlorinated hydrocarbons, benzene, toluene, xylene, lower aliphatic hydrocarbons, and the like may advantageously be used as reaction ~olvents. Examples of such solvents are methanol, ethanol, n-propanol, iqopropanol, butanol, pentanol, acetone, methylethyl ketone, diethylketone, methyl acetate, ethyl acetate, chloroform, methylene chloride, dichloroethane, hexane, heptane, octane, decane, and the like. If a D~PA or EDTA-type acid chloride i~ used a~ the starting material, then the reaction solvent advantageously is one which does not contain reactive functional groups, such a~ hydroxyl groups, as these ~olvents can react with the acid chloride~, thus producing unwanted by-products.
The reaction temperature may vary widely, depending upon the starting materials employed, the nature of the reaction solvent and other reaction condition~. Such reaction temperature~ may xange, for example, from about 20C to about 85C, preferably from about 25C to about 50C.
Following reaction of the reactive polyaminocarboxylic acid derivative~ with the hydr~zine compound, any r0mainir-g anhydride or acid chloride groups can be hydrolyzed to the carboxylate group~ by adding a stc)ichiometric excess of water to the reaction mixture and heating for a short time.
The rQsulting hydrazide is recovered from the reaction mixture by conventional procedures. For example, the product may be precipitated by adding a precipitating solvent to the reaction mixture, and recovered by filtration or centrifugation.

The paramagnetic ion is combined with the hydrazide under complex-forming conditions. In general, any of the paramagnetic ions referred to above can be employed in making the complexe~ of thi~ invention. The complexes can conveniently be prepared by mixing a suitable oxide or salt of the paramagnetic ion with the complexing agent in aqueous solution. To assure complete complex fermation, a slight stoichiometric exce~6 of the complexing agent may be used. In addition, an elevated temperature, e.g., ranging from about 20C to about 100C, preferably from about 40C
to about 80C, may be employed to insure complete complex formation. Generally, complete complex formation will occur within a period from a few minutes to a few hour~ after mixing. The complex may be recovered by precipitation using a precipitating solvent such as acetone, and further purified by crystallization, if desired.
The novel complexes of this invention can be formulated into diagnostic compositions for enteral or parenteral administration. These compositions contain an effectiv~ amount of the paramagnetic ion complex along with c:onventional pharmaceutical carriers and excipients appropriate for the type of admlnistratlon contemplatecl. For example, parenternl formulatlons advantageou~ly contain a ~terll~ ~queou~ ~olution ox su~pension of from about 0.05 to l.OM of a paramagnetic ion complex according to this invention. Preferred parenteral formllations have a concentration of paramagnetic ion complex of O.lM to O.SM. Such solutions Also may contain pharmaceutically acceptable buffers and, optionally, elQctrolytes such a~ sodium chloride. The compositions may advantageouRly contain a slight exce~s, e.g., from about 0.1 to about 15 mole 2~J~

% excess, of the complexing agent or its complex with a physiologically acceptable, non-toxic cation to insure that all of the potentially toxic paramagnetic ion is complexed. Such physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zînc ions and the like. Calcium lons are preferred. A typical single dosage formulation for parenteral administration has the following composition:
Gadolinium DTPA-bis~hydrazide)330mg/ml Calcium DTPA-bis(hydrazide)14mg/ml Distilled Water q.6. to 1 ml pH 7.0 Parenteral compositlons may be in~ected directly or mixed with a large volume parenteral composition for systemic administration.
Formulations for enteral administration may vary widely, as i8 well-known in the art. In general, such formulation~ are liquids which include an effective amount of the paramagnetic ion complex in aqueous solution or suspen&ion. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may al60 contain flavorlng agents and other ingredlents for enhancing their organoleptic qualities.
The diagno6tic compositions are adminlstered in doses effective to achieve the desired enhancement of the NMR image. Such doses may vary widely, depending upon the particular paramagnetic ion complex employed, the organs or tissues which are the sub~ect of the imaging procedure, the NMR imaging equipment being used, etc. In general, parenteral dosages will range from about 0.01 to about 1.O MMol of paramagnetic ion 2 ~ ~ 1 3 1 3 complex per kg of patient body weight. Preferred parenteral do~ages range from about 0.05 to about 0.5 MMol of paramagnetic ion complex per kg of patient body weight. Enteral do~ages generally range from about O.S
S to about lO0 MMol, preferably from about 1.0 to about 20 MMol of paramagnetic ion complex per kg of patient body weight.
The novel NMR image contrasting agents of this invention possess a unique combinativn of desirable feature~. The paramagnetic ion complexes exhibit an unexpectedly high 601ubility in physiological fluids, notwithstanding their substantially non-ionic character. This high solubility allows the preparation of concentrated ~olution~, thus minimizing the amount of fluid required to be administered. The non-ionic character of the complexes also reduces the osmolality of the diagnostic composition6, thus preventing undesired edema and other side effects. As illustrated by the data presented below, the compos$tions of this invention have very low toxicitie~, as reflected by their hiqh LD~o values.
The diagnostic compositions of this invention are used in the conventional manner. The compos1tions may be admini~tered to a warm-blooded animal either systemically or locally to tho orgnn or tis~ue to be imaged, and the animal then sub~ected to the NMR
imaging procedure. The compositions have been found to enhance the magnetic re~onance images obtained by these procedures. In addition to their utility in magnetic resonance imaging procedures, the complexing agents of this invention may al~o be employed for del,ivery of radiopharmaceuticals or heavy metals for x-ray contrast into the body.

2 ~ ?s~

The invention i8 further illustrated by the following example~, which are not intended to be limiting.

~ ~J ~3 Example I
o / ~
N O

¦ O H2N-N-Me2 ~N ~
\ ~ / \ iPrOh, 50C .

~O

,,--CO2H CH~
r~ ~ -CONH-N

Gd20~

CO2H ~ CO2H CH3 >
~N / HzO, 65C
--CONH-N

{ 2 CH3 N
~ --~ONH - N
~~ 3 CH3 (~2 --CONH-N

CH~

2 ~

Preparation of [N,N" -ai8 ( 2,2-dimethylhydrazino)-carbamoylmethyl]diethylene-triamine-N,N',N"-triacetic acid:
A mixture of DTPA-dianhydride (10 g) and N,N-dimethylhydrazine t3.7 g) in isopropanol (25 mL) wasstirred at 50C (water bath) for 18 hours. The gummy residue was di~solved by the addition of 50 mL of methanol and the solution filtered through a fine poro~ity sintered glass funnel to remove undissolved impurities. The solvent wa~ removed under reduced pressure and the solid was recrystallized from 95~
ethanol/isopropanol to give 5.3 g of colorless solid (m.p. 142-144C). Anal. Calcd. for Cl3H,5N70a x 1.5 H20s C, 42.86; H, 7.54; N, 19.44. Founds C, 43.03; H, 7.52; N, 18.91.
Preparation of [N,N'-Bis(2,2-dimethylhydrazino)-carbonylmethyl]diethylenetriamine-N,N', N"-triaceto]
gadolinium (III) hydrate (MP-1291).
A mixture of the ligand (9.4 g) and gadolinium oxide (3.3 g) in deionized, distilled water (50 mL) was he2ted ~t 65-70C for 20 hours. The pale green solution was filtered through a fine porosity sintered gla~s funnel to remove undissolved impurities. ~he clear filtrate was then poured onto acetone (lL) and the ~olid W~18 collected and dried. The off whlte solid was redi~solved in water (25 mL) ~nd puri1ed by flash chromatogralphy over rever~e phase (o~tadecyls~lane derivatized ~ilica gel) sorbent to give almost colorles~ ~olid. Yield 10.3 g (88~). Anal. Calcd. for C,8H32N70~Gd x H20. C, 31.79; H, 4.91; N, 11.58; Gd, 26.01. Found~ C, 31.89; H, 4.89; N, 11.45; Gd, 25.70.

Example II
The acute intravenous toxLcity of the compound of Example 1 was determined as follows: ICR mice, at 1 to 2~5i~1a 1~

4 per dose level, received ~ingle intravenous in~ection~ of the ~est substance via a lateral tail vein at the rate of approximately 1 ml/minute. The test sub~tances were at concentrations cho~en to result in dose volumes of 5 to 75 ml/kg body weight. Do~ing began at a volume of 10 ml/kg. Dose ad~ustments up or down were made to closely bracket the estimated LDso with 4 animals per group (2 males and 2 females).
Observations of the mice were recorded at times 0, 0.5, 1, 2, 4 and 24 hours and once daily thereafter for up to 7 days post in~ection. On the 7th day post in~ection, the mice were euthanized, weighed and necropsied. Abnormal tissues wexe noted. At thi~ time a decision was made as to whether any histopathology was to be perfo~ned and whether or not the tissues should be re~ained. Necropsies were also performed on mice expiring after 24 hours post-in~ection, except for dead mice found on the weekend~. The LD~o value~, along with 95% CI were calculated using a modified ~ehrens-Reed-Meunch method. The re~ults for the complex of Example 1 are reported below:
LD50: 11.5 mmol/kg 95~ Confidence Limits: 6.8-19.6 mmol/kg Sex and Wei~ht Range of Mice: Males (15.5-22.7 g) Females ~19.6-20.3 g) Example III

Tl relaxation times were measured using spin-echo sequence on the JEOL FX9OQ (90 MHz) FT-NMR
4pectrometer/ Twenty millimolar solution of the complex in Example 1 wa~ prepared in H20/DzO (4:1) mixture and was serially diluted to lower concentrations (10, 5, 2.5, 1.25, 0.526 mM) with 1 9 2 ~

H2O/D2O (4:1) mixture. T~ mea6urement~ were made at each of these 6 concentrations. The relaxivity (Rl) was determined by applying least-square fit to the plot of 1/TI versu~ concentration. The r~laxivity of tho complex in Example 1 was 4.85+0.06 mM~~6ec~l. The correlatlon coefficient for the least Bquare8 analy8i8 was O 9994 -

Claims (42)

1. The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:
   
   l. A complex having the following formula:
   
   wherein A is -CHR2-CHR3- or M+Z is a paramagnetic ion of an element with an atomic number of 21-2:3, 42-44 or 58-70, and a valence, Z, of +2 or +3; R1 groups may be the same or different, and are selected from the group consisting of -O- and wherein R4, R5, and R6 may be the same or different and are hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms, or R5 and R6 can together with the adjacent nitrogen form a heterocyclic ring of five, six or seven members, wherein 0 to 1 members other than the nitrogen are -O-, -S- -?- or -?- and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms, or R4 and R5 can together with the nitrogens to which each is attached form a heterocyclic ring of five, six or seven members, wherein 0 or 1 members other than the nitrogens are -O-, -S-, or and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms;
   R7 and R1 may be the same or different and are hydrogen, alkyl having from 1 to about 6 carbon atoms, phenyl or benzyl;
   R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms;
   and wherein 2 or 3 of the R1 groups are -O- and the remainder of the R1 groups are
2. 2. The complex of claim 1, wherein A is
3. 3. The complex of claim 1, wherein A is -CHR2CHR3-and R2 and R3 are both hydrogen.
4. 4. The complex of claim 1, wherein M+z is praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
5. 5. The complex of claim 4, wherein M+z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
6. 6. The complex of claim 2, wherein R1 is dimethylhydrazide and M+z is gadolinium (III).
7. 7. The complex of claim 1 wherein R5 and R6 together form a heterocyclic ring of the formula wherein X is a single bond, -CH2-, -O-, or .
8. 8. The complex of claim 7 wherein X is -O-.
9. 9. The complex of claim 7 wherein X is -CH2-.
10. 10. The complex of claim 7 wherein X is a single bond.
11. 11. The complex of claim 1 wherein R4 and R5 together form a heterocyclic ring of the formula or .
12. 12. A diagnostic composition suitable for enteral or parenteral administration to a warm-blooded animal, which comprises an NMR imaging-effective amount of a complex of a paramagnetic ion having the following formulas wherein A is -CHR2-CHR2- or M+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of +2 or +3; R1 groups may be the same or different and are selected from the group consisting of -O- and wherein R4, R5, and R6 may be the same or different and are hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms, or R5 and R6 can together with the adjacent nitrogen form a heterocyclic ring of five, six or seven members, wherein 0 to 1 members other than the nitrogen are -O-, -S-, -?- or -?- and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms, or R4 and R5 can together with the nitrogens to which each is attached form a heterocyclic ring of five, six or seven members, wherein 0 or 1 members other than the nitrogens are -O-, -S-, or and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms;
    R2 and R3 may be the same or different and are hydrogen, alkyl having from 1 to about 6 carbon atoms, phenyl or benzyl;
    R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms;
    
    and wherein 2 or 3 of the R1 groups are -O- and the remainder of the R1 groups are and a pharmaceutically acceptable carrier.
13. 13. The composition of claim 12, wherein A is
14. 14. The composition of claim 12, wherein A is -CHR2CHR1- and R2 and R3 are both hydrogen.
15. 15. The composition of claim 12, wherein M+z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
16. 16. The composition of claim 15, wherein M+z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
17. 17. The composition of claim 16, wherein R is dimethylhydrazide and M+z is gadolinium (III).
18. 18. The composition of claim 17, which further contains a pharmaceutically acceptable buffer.
19. 19. The composition of claim 18, which further contains a pharmaceutically acceptable electrolyte.
20. 20. The composition of claim 14, which further comprises a stoichiometric excess of a complexing agent of the formula wherein A and R1 are as defined as in claim 14.
21. 21. The composition of claim 20 wherein said excess complexing agent is complexed with a physiologi-cally acceptable, non-toxic cation.
22. 22. The composition of claim 21, wherein said excess complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % excess, relative to the paramagnetic ion, and is complexed with a cation selected from the group consisting of calcium ions, magnesium ions, copper ions and zinc ions.
23. 23. The composition of claim 22, wherein said excess complexing agent is complexed with calcium ions.
24. 24. A method of performing an NMR diagnostic procedure, which comprises administering to a warm-blooded animal an effective amount of a complex of the formula wherein A is -CHR2-CHR3- or M+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of +2 or +3; R1 groups may be the same or different and are selected from the group consisting of -O- and wherein R4, R5, and R6 may be the same or different and are hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms, or R5 And R6 can together with the adjacent nitrogen form a heterocyclic ring of five, six or seven members, wherein 0 or 1 members other than the nitrogen are -O-, -S-, -?- or -?- and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms, or R4 and R5 can together with the nitrogens to which each is attached form a heterocyclic ring of five, six or seven members, wherein O or 1 members other than the nitrogens are -O-, -S-, or and which members are unsubstituted or substituted by hydroxy, alkyl, aryl, hydroxyalkyl, aminoalkyl, aminoaryl, alkylamino, or carbamoyl wherein the substituents contain from 1 to about 6 carbon atoms;
    R2 and R3 may be the same or different and are hydrogen, alkyl having from 1 to about 6 carbon atoms, phenyl or benzyl;
    R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl or acylaminoalkyl wherein the carbon-containing portions contain from 1 to about 6 carbon atoms;
    and wherein 2 or 3 of the R1 groups are -O- and the remainder of the R1 groups are ;
    
    and then exposing the animal to an NMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal.
25. 25. The method of claim 24, wherein A is
26. 26. The method of claim 24, wherein A is -CHR2CHR3- and R2 and R3 are both hydrogen.
27. 27. The method of claim 24, wherein M+z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
28. 28. The method of claim 27, wherein M+z is gadolin-ium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).
29. 29. The method of claim 28, wherein R1 is dimethylhydrazide and M+z is gadolinium (III).
30. 30. The method of claim 29, wherein the pharma-ceutically acceptable carrier contains a pharmaceutically acceptable buffer.
31. 31. The method of claim 29, wherein the pharma-ceutically acceptable carrier contains a pharmaceutically acceptable electrolyte.
32. 32. The method of claim 25, wherein the pharma-ceutically acceptable carrier contains a stoichiometric excess of a complexing agent of the formula wherein A and R1 are as defined as in claim 24.
33. 33. The method of claim 32, wherein said excess complexing agent is complexed with a physiologically acceptable, non-toxic cation.
34. 34. The method of claim 33 r wherein said excess complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % excess, relative to the paramagnetic ion, and is complexed with a cation selected from the group consisting of calcium ions, magnesium ions, copper ions and zinc ions.
35. 35. The method of claim 34, wherein said excess complexing agent is complexed with calcium ions.
36. 36. A complexing agent of the formulas wherein A is -CHR2-CHR3- or and X is a single bond, -CH2-, -O-, -S-, or wherein R1, R2, R3 and R7 are defined as in claim 1.
37. 37. The complexing agent of claim 36, wherein A is
38. 38. The complexing agent of claim 36, wherein A is -CHR2CHR3- and R2 and R3 are both hydrogen.
39. 39. The complexing agent of claim 37 wherein X
    is -O-.
40. 40. The complexing agent of claim 37 wherein X
    is -CH2-.
41. 41. The complexing agent of claim 37 wherein X is a single bond.
42. 42. A complexing agent of the formula wherein A is -CHR2-CHR3- or and R1, R2, R3 and R6 are as defined in Claim 1.